This invention relates to the binding of L-tryptophan to human serum albumin in a biological fluid, and in particular to a method of inhibiting this binding.
Serum albumin is the most abundant plasma protein. It's major functions are regulation of osmotic pressure and transport of a wide variety of drugs (usually carrying a negative charge), and endogenous substances such as bilirubin, fatty acids and L-tryptophan (L-TRP). It is clear that although albumin can bind a wide variety of molecules there are only three sets of binding sites selected by evolution for the transport of (i) nutrients (i.e. fatty acids), (ii) waste (i.e., bilirubin), and (iii) precursor of neurotransmitters (i.e., L-TRP).
It has been shown, for example, in Soltys, B. and Hsia, J. C. (1978) J. Biol. Chem. 253: 3029, that the binding of a molecule to one site can allosterically modulate the binding of a second molecule to a distant site as a result of conformational change of the albumin molecule. Thus, it is important to understand the binding specificity and mechanism of albumin so that the availability of nutrients, hormones and drugs can be modulated to regulate restorative processes, for example, onset and quality of sleep, in man.
It is known, for example, from Gessa, G. L. and Tagliamonte, A. (1974) In: Aromatic amino acids in the brain, Elsevier Publ., Amersterdam, 1974, that L-tryptophan is the precursor of serotonin and its increase in plasma concentration will enhance brain L-TRP levels and presumably brain serotonin levels as well. Serotonin is a neurotransmitter and is involved in a number of physiological processes including influence on sleep. For example, it has been shown in Hartmann, E. (1972) J. Pharm. Pharmacol. 24: 252 that administration of L-TRP reduces latency to sleep, and in Hill, S. Y. and Reyes, R. B. (1978) Psychopharmacol. 58: 229 to induce REM latency in rats.
Because of high albumin concentrations in plasma, the majority of L-TRP is albumin-bound under physiological conditions. It is thus postulated that displacement of L-TRP from albumin will raise the free plasma level of L-TRP and brain serotonin levels which consequently influence the onset or quality of sleep.
It is thus an object of the invention to inhibit the binding of L-TRP to serum albumin by providing a modulator which competes with L-TRP for the same binding site on serum albumin, the modulator having a higher affinity than L-TRP for albumin.